Dialysis solution, formulated and stored in two parts, comprising phosphate

ABSTRACT

The present invention relates to a medical solution. According to the invention the ready-for-use solution comprises phosphate in a concentration of 1.0-2.8 mM, is sterile and has a pH of 6.5-7.6. The present invention further relates to a method for producing the medical solution and the use thereof.

TECHNICAL FIELD

The present invention relates to a medical solution, a method forproducing and use thereof. Particularly the present invention relates toa medical solution for dialysis.

BACKGROUND OF THE INVENTION

Dialysis is the indicated treatment for patients whose kidney functionis failing. The removal of waste substances from the blood is effectedby transfer to an external fluid or replacement of plasma liquid by anexternal fluid. Various dialysis techniques, with associated dialysisfluids, can be differentiated, which are used depending on the type ofpatient. In the case of patients suffering from long-term renalinsufficiency, the dialysis technique used is usually an intermittenttreatment of few times (2 to 3 times) per week for a few hours (3 to 5hours). With this technique, known as hemodialysis, waste substances, inparticular urea, salts and other small molecules, are removed from theblood by means of diffusion through a semi-permeable membrane. Anotherform of dialysis is peritoneal dialysis. In contrast to hemodialysis,where the blood is passed over a dialysis fluid in a dialysis unit(artificial kidney) outside the body, in the case of peritoneal dialysisa dialysis fluid is introduced into a patient's abdominal cavity(peritoneum), wherein the peritoneum is acting as a semi-permeablemembrane.

In the case of patients suffering from acute renal insufficiency, acontinuous treatment, throughout the entire day for several weeks, acontinuous renal replacement therapy (CRRT), is the indicated treatment.A technique other than hemodialysis, specifically hemofiltration, isused for this. In the case of hemofiltration, waste substances areremoved from the blood by means of convective flow through a highlypermeable membrane. In this way the above-mentioned waste substances areremoved in larger amounts and large(r) molecules are also removed. Inaddition, in the case of hemofiltration and appreciable quantity ofliquid, which can vary from 1 to 5 liters per hour, is removed from thebloodstream. In contrast to hemodialysis, this demands that in the caseof hemofiltration a replacement fluid must be returned to the patient inlarge quantities. Optionally a combination of dialysis and filtrationcan be used. This is called hemodiafiltration. A specific type ofhemodiafiltration is continuous veno-venous hemodiafiltration,abbreviation as CVVHDF.

Under certain circumstances, in patients receiving regular thrice-weeklyhemodialysis treatments and more frequently in patients undergoing CRRTHypophosphatemia could occur. In the first case it is mainly due to anexcessive ingestion of phosphate binders, inadequate administration ofphosphate salts in parenteral nutrition and continued removal ofphosphorus by dialysis. In the second case it is mainly a consequence ofthe efficient removal of phosphorus from patients having normal renalfunction from the beginning and thus a normal serum phosphorus level.

Hypophosphatemia is prevented and treated principally via the oral andthe intravenous routes, for example by ingestion of phosphorus-richfoodstuffs, by oral phosphorus preparations or by intravenousadministration of sodium (or potassium) phosphate salts. However theadministration of phosphorus via oral and intravenous routes must becarried out with great caution, since it is impossible to determine theprecise magnitude of the total phosphorus deficit, it is difficult todecide the correct amount of phosphorus to be administered to thepatient. If too much phosphorus is administered hyperphosphatemia mightdevelop, having serious consequences for the patient, for examplehypocalcaemia, metastatic calcification and hypotensions, and if toolittle phosphorus is administered the hypophosphatemia is not corrected.

The use of solution containing both calcium ions and phosphate is usedin solutions for total parenteral nutrition (TPN). The TPN solutions ispacked in multi-compartment bags with lipids in a first compartment,amino acids and phosphate and most of the electrolytes except calcium ina second compartment, and a third compartment containing calcium andglucose. The main difference compared to a medical solution according tothe invention is that the pH of the final, ready-for-use solutions ismuch lower than in the solutions showed in this invention, The TPNsolutions normally have a pH between 5.2-6.

In U.S. Pat. No. 6,743,191 a substitution infusion fluid is disclosed,which infusion fluid comprises among other 0.2-1.0 mM dihydrogenphosphate ions, preferably 0.5-0.9 mM, and 1.6-2.6 mM calcium ions,preferably 1.9-2.4. The substitution infusion fluid according to thisdisclosure may conveniently be prepared by dissolving salts in water insuch amounts that the desired concentrations are reached, as is wellwithin the expertise of the normal person skilled in the art. During thepreparation it is desired that a sterile environment be maintained.

In U.S. Pat. No. 6,017,942 an intravenous solution for treating patientwith chronic renal failure is disclosed, which solution comprises amongother approximate 0-20 mM phosphate and approximate 0-10 mM calcium.This solution is to be administered 1-3 times per day.

The problem when introducing phosphorus in a medical solution is theformation of various calcium phosphates that precipitate and the riskfor precipitation is further increased if the fluid is exposed toterminal heat sterilization. The solubility of calcium phosphatesdepends on the concentrations of calcium and phosphate, respectively,and further on the presence of other electrolytes, temperature and pH.As long as the pH is about 5.2-6, as in the TPN solutions, there is norisk of precipitation, but in physiological solutions with pH valuesequal to physiological pH of about 7-7.6, the risk of precipitation isenhanced. Accordingly, it is not only the pH during sterilization andstorage that need to be controlled, also the pH in a mixed andready-for-use solution needs to be controlled. The problem is also thatmany of these fluids should be stable during long-term storage, up totwo years.

In one of the above-identified references this is solved by having thecomposition for the solution as a powder up until use and then dissolveit in a fluid before administration. However, even if trying to maintainsterility according to the European pharmacopoeia to thereby avoid therisk of infection in a patient, this is not an optimal way to maintainsterility. If a package is brought in connection with the atmosphere bye.g. injecting a solution component into a bag with a solution, thissolution is no longer a sterile solution. Instead it is an asepticsolution, and aseptic solutions as such are not allowed to be infusedinto a patient.

The best way would be to have the solution terminal sterilized in itspackaging in order to make sure that the solution is as sterile aspossible and to be kept in this sterile environment also during mixinginto a ready-for-use solution without opening up the bag and expose thecontent therein for contamination.

SUMMARY OF THE INVENTION

One object of the invention is to provide a medical solution thatensures good stability, both during storage and during use, thatcontains no precipitates and is sterile.

The present invention relates to a medical solution. According to theinvention the ready-for-use solution comprises phosphate in aconcentration of 1.0-2.8 mM, is sterile and has a pH of 6.5-7.6.

In one embodiment of the invention, said medical solution, in it's stateof ready-for-use solution, comprises phosphate in a concentration of1.2-2.6 mM and has a pH of 6.5-7.6.

In another embodiment said medical solution, in it's state ofready-for-use solution, comprises phosphate in a concentration of up toabout 2.8 mM and has a pH of 6.5-7.4.

In another embodiment said medical solution, in it's state ofready-for-use solution, comprises phosphate in a concentration of up toabout 1.3 mM and has a pH of 6.5-7.6.

In a further embodiment the medical solution is divided into at leasttwo single solutions before use, wherein a first single solutioncomprises at least one buffer chosen from the group comprising acetate,lactate, citrate, pyruvate, carbonate and bicarbonate and a secondsingle solution comprises an acid, wherein said first and second singlesolutions, after terminal sterilization and up on use, are to be mixedto form a ready-for-use solution, and wherein said ready-for-usesolution has a pH of 6.5-7.6.

In another embodiment said second single solution has a pH below 2.5.

In another embodiment said first single solution comprises bicarbonateand carbonate in such proportions that the partial pressure of carbondioxide, CO₂, in said first single solution is of the same order ofmagnitude as the partial pressure of carbon dioxide, CO₂, of theatmosphere, and said second single solution has a pH of 1.0-1.5, andsaid ready-for-use solution has a pH of 7.0-7.6.

In even an additional embodiment said first single solution has a pH of10.1-10.5, preferably 10.3.

In another embodiment said second single solution has a pH of 1.3.

In another embodiment said second single solution comprises HCl.

In another embodiment said first single solution comprises the phosphateions.

In another embodiment said second single solution comprises thephosphate ions.

In a further embodiment said ready-for-use solution further comprisesone or more electrolytes, wherein said one or more electrolytes compriseone or more of the ions of sodium, calcium, potassium, magnesium and/orchloride. Said one or more electrolytes is/are before being mixed intothe ready-for-use solution, arranged in said second single solution. Inone embodiment sodium ions and/or chloride ions are, before being mixedinto the ready-for-use solution, arranged both in said first and saidsecond single solution.

In a further embodiment said first single solution comprises bicarbonateand phosphate, and said second single solution comprises calcium and/ormagnesium.

In even a further embodiment said first single solution compriseslactate and phosphate, and said second single solution comprises calciumand/or magnesium.

In another embodiment said second single solution further comprisesglucose.

The present invention further relates to a method for producing amedical solution. According to the invention, said method comprisesproviding said single solutions in separate compartments, and thereafterterminal sterilizing said single solutions.

The present invention further relates to a multi-compartment bagcomprising the medical solution according to the invention.

Further the present invention relates to the use of a medical solutionaccording to the invention.

Additional objects, features, advantages and preferred embodiments ofthe present invention will become apparent from the following detaileddescription when taken in conjunction with the enclosed patent claims.

Definitions

The term “medical solution” is intended to mean dialysis solutions forhemodialysis, hemodiafiltration, hemofiltration, and peritonealdialysis, solutions for dialysis within renal intensive care, solutionsfor substitution or infusion normally containing buffering substances,and solutions for nutrition purposes.

The term “single solution” is intended to mean one solution keptisolated from other solutions up until use.

The term “bicarbonate and carbonate” is intended to mean alkalibicarbonate and alkali carbonate, especially sodium bicarbonate andsodium carbonate.

The term “a ready-for-use solution” is intended to mean a solution whichincludes the required different single solutions and which is ready foruse.

The term “multi-compartment bag” is intended to mean a bag divided intomore than one compartment and that the content in the differentcompartments could be brought together and mixed before use.

The term “terminal sterilization” is intended to mean that the productis sterilized in its final package. The terminal sterilization mayinclude heat sterilization and/or radiation sterilization, but ispreferably heat sterilization effected in an autoclave at a temperatureof at least 100° C., preferably at least 121° C.

The term “up on use” is intended to mean as close as possible before themedical solution is used for it's specific purpose.

The term “glucose or glucose-like compounds” is intended to meanglucose, polymers of glucose such as cellulose and starch as well asother molecules containing at least on glucose unit i.e. disaccharides,trisaccharides and polysaccarides (glycans).

BRIEF DESCRIPTION OF THE DRAWING(S)

FIGS. 1A-C are graphs showing the relationship between pH value in thefinal ready-for-use solution and the amount produced particles 24 hoursafter mixing for a solution containing 1.3 mM phosphate.

FIGS. 2A-C are graphs showing the relationship between pH value in thefinal ready-for-use solution and the amount produced particles 24 hoursafter mixing for a solution containing 2.6 mM phosphate.

FIGS. 3A-C are graphs showing the relationship between phosphateconcentration and the amount of produced particles 24 hours after mixingfor a solution having a pH of 7.6.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention have found that during specificcircumstances, concentrations, pH ranges and packaging, a sterile,stabile phosphate containing medical solution could be provided, and itis this which constitute the base for the present invention.

One of the more important matters searching for the most favorablecircumstances, concentrations, pH ranges and packaging is the formationof particles during production, storage and preparation for aready-for-use solution. The amount of particles has to stay in betweenspecific ranges both concerning the size of the particles as well as theamount of particles. This is specified within the EuropeanPharmacopoeia, and for particles in the size of 10 μm the limit is 25counts/ml. It is very important that the particle formation is kept to aminimum, otherwise the immune system could get triggered, which couldlead to start of the inflammatory cascade. A further problem with thepresence of particle is the risk of clogging the filters, which are usedduring the dialysis treatment.

The main components that give rise to the problem of particle formationare calcium ions in combination with either carbonate and/or phosphate.

The first instant thought to solve the problem is of course to keepcalcium ions separated from carbonate and phosphate during productionand storage, but the problem is still there when preparing theready-for-use solution, whereby the formation of solid calcium carbonateand calcium phosphate still could be formed during mixing.

The present inventors have found that, with a phosphate concentration ofup to about 2.8 mM in the ready-for-use solution, the amount of formedparticles are within the allowed limits if the pH value in theready-for-use solution is kept to at most 7.4, preferably at most 7.2.

If the phosphate concentration is up to about 1.3 mM in theready-for-use solution an allowed amount of particles are formed if thepH value in the ready-for-use solution is kept to at most 7.6,preferably at most 7.4.

The present inventors have also found that calcium and phosphate couldbe kept together during preparation and storage if these two componentsare kept in a compartment with a pH below 2.5, preferably below 1.5, andmost preferably below or equal to 1.3.

In one embodiment of the invention the medical solution is before usedivided into at least two single solutions, a first single solution anda second single, wherein said first and second single solutions, afterterminal sterilization and up on use, are to be mixed to form a finalsolution with a pH of 6.5-7.6.

Said first single solution comprises at least one buffer chosen from thegroup comprising acetate, lactate, citrate, pyruvate, carbonate andbicarbonate and said second single solution comprises an acid.

In another embodiment of the invention said first single solutioncomprises bicarbonate and carbonate in such proportions that the partialpressure of carbon dioxide, CO₂, in the first single solution is of thesame order of magnitude as the partial pressure of carbon dioxide, CO₂,of the atmosphere. Bicarbonate and carbonate are preferably mixed assodium bicarbonate and sodium carbonate, and in one embodiment saidfirst single solution has a pH within the range of 10.1-10.5, preferably10.3.

By adjusting the partial pressure of carbon dioxide, CO₂, in the firstsingle solution in the same order of magnitude as the partial pressureof carbon dioxide, CO₂, in the atmosphere, the carbon dioxide in thecompartment for the first single solution stays within the bagcompartment and does not enter out of the bag material out into theatmosphere, as the partial pressure of CO₂ within the liquid is inequilibrium with the partial pressure of CO₂ in the atmosphere.

After having mixed said first and second single solutions in thisembodiment into a ready-for-use solution, said ready-for-use solutionhas a pH within the range of 7.0-7.6. Further, said ready-for-usesolution preferably has a bicarbonate concentration of at least 25 mM,preferably at least 30 mM, and at most 45 mM, preferably at most 40 mM.

However, the combination of bicarbonate/carbonate in said first singlesolution could in another embodiment, as stated above, be exchanged toor supplemented by one or more of the buffers chosen from the groupcomprising acetate, lactate, citrate and pyruvate. In one embodiment,the buffer is bicarbonate in a concentration of 25-35 mM with optionally0-15 mM lactate added, wherein the concentration given is theconcentration in the ready-for-use solution.

In one embodiment said second single solution preferably has a pH withinthe range of 1.0-1.5, most preferably a pH of 1.3. In one embodiment ofthe invention said second single solution comprises HCl.

In one embodiment said ready-for-use solution further comprises one ormore electrolytes. The electrolytes are one or more of the ions ofsodium, calcium, potassium, magnesium and/or chloride. The arrangementof the electrolytes in the different compartments is dependent on thedifferent electrolytes co-behavior with the other substances present insaid single solutions, i.e. whether some sort of reaction could occurbetween one or more of the electrolyte(s) and the other substancespresent in a specific single solution. Usually, the electrolytes arecontained in said second single solution. For example, calcium ions andmagnesium ions are preferably provided in any of the other singlesolutions, but said first single solution when said first singlesolution comprise the combination of bicarbonate/carbonate, onlybicarbonate and/or phosphate. The reason for this is that calcium andmagnesium and bicarbonate/carbonate, bicarbonate and/or phosphatetogether could cause precipitation of calcium carbonate, magnesiumcarbonate, calcium phosphate and magnesium phosphate. However, calciumions and magnesium ions could be kept with bicarbonate under certaincircumstances, such as specific pH ranges and so on, this is for exampledisclosed in EP 0 437 274, which hereby is enclosed by reference.Further calcium and magnesium could be kept with phosphate also undercertain circumstances, see above of this.

Sodium ions and/or chloride ions, on the other hand, are usuallyarranged in both said first and said second single solutions.

Said medical solution could further comprise glucose or glucose-likecompounds, and in one embodiment the glucose or glucose-like compoundsis arranged in said second single solution. During sterilization andstorage glucose or glucose-like compounds should be kept at a low pHvalue in order to ensure that the formation of glucose degradationproducts (GDPs) are kept to a minimum. In one embodiment the pH in thesecond single solution is below 2.5.

In the method for producing a medical solution according to above, saidsingle solutions are provided in separate compartments. Thereafter saidsingle solutions are terminally sterilized. Preferably, the terminalsterilization is heat sterilization and/or radiation sterilization, (seealso European Pharmacopoeia 1977 for a review of different sterilizationtechniques). In one embodiment of the method according to the invention,the terminal sterilization is heat sterilization at a temperature of atleast 100° C., preferably at least 121° C.

The sterilization time may vary depending on the sterilizationtemperature, the type of container and the contents therein to besterilized.

The radiation sterilization may be either ionising or non-ionisingsterilization. Examples of ionising sterilization are gamma and betaradiation. Examples of non-ionising radiation sterilization is UVradiation.

The medical solution according to the present invention has theadvantage of ensuring good stability and good biocompatibility.

Said single solutions could be provided in different compartments in amulti-compartment bag, and the mixing could be provided by having thedifferent compartments coupled by frangible pins, which pins could bebroken in order to mix the content in the different compartments withinthe multi-compartment bag. The mixing could further be provided byhaving a peal seal in-between the different compartments, which pealseals could be pealed in order to mix the content in the differentcompartments.

EXAMPLES

Below you will find different examples of solutions according to thepresent invention.

Example 1

The following pairs of single solutions were prepared according to thetable 1-5 below. The volume relationship between the first singlesolutions and the second single solutions are 1:20.

TABLE 1 (solution 1) First single solution Second single solution (basicpart) (acid part) (mM) (mM) Na⁺ 1461.0 70.5 Cl⁻ — 113.6* Ca²⁺ — 1.8 Mg²⁺— 0.5 HCO₃ ⁻ 139.0 — CO₃ ²⁻ 661.0 — H₂PO₄ ⁻ — — *Chloride ions have beenadded as NaCl, CaCl₂, MgCl₂, and HCl.

TABLE 2 (solution 2) First single solution (basic part) Second singlesolution (mM) (acid part) (mM) Na⁺ 1487.0 70.5 Cl⁻ — 113.6* Ca²⁺ — 1.8Mg²⁺ — 0.5 HCO₃ ⁻ 139.0 — CO₃ ²⁻ 661.0 — H₂PO₄ ⁻ 26 — *Chloride ionshave been added as NaCl, CaCl₂, MgCl₂, and HCl.

TABLE 3 (solution 3) First single solution (basic part) Second singlesolution (mM) (acid part) (mM) Na⁺ 1513.0 70.5 Cl⁻ — 113.6* Ca²⁺ — 1.8Mg²⁺ — 0.5 HCO₃ ⁻ 139.0 — CO₃ ²⁻ 661.0 — H₂PO₄ ⁻ 52 — *Chloride ionshave been added as NaCl, CaCl₂, MgCl₂, and HCl.

TABLE 4 (solution 4) First single solution (basic part) Second singlesolution (mM) (acid part) (mM) Na⁺ 1461.0 71.8 Cl⁻ — 113.6* Ca²⁺ — 1.8Mg²⁺ — 0.5 HCO₃ ⁻ 139.0 — CO₃ ²⁻ 661.0 — H₂PO⁴⁻ — 1.3 *Chloride ionshave been added as NaCl, CaCl₂, MgCl₂, and HCl.

TABLE 5 (solution 5) First single solution (basic part) Second singlesolution (mM) (acid part) (mM) Na⁺ 1461.0 73.1 Cl⁻ — 113.6* Ca²⁺ — 1.8Mg²⁺ — 0.5 HCO₃ ⁻ 139.0 — CO₃ ²⁻ 661.0 — H₂PO₄ ⁻ — 2.6 *Chloride ionshave been added as NaCl, CaCl₂, MgCl₂, and HCl.

The solutions were sterilized in an autoclave at 121° C. for 40 minutes.After sterilization, the first and second solution in each pair weremixed and the amounts of particles in the sizes 2, 5 and 10 μm,respectively, were measured. The results are presented in table 6 below.

TABLE 6 Mixed ready-for-use solution Particles (mM) counts/ml Na⁺ Cl⁻Ca²⁺ Mg²⁺ HCO₃ ⁻ CO₃ ²⁻ H₂PO₄ ⁻ 2 μm 5 μm 10 μm Solution 1 143.6 108.01.7 0.5 6.9 33.0 — 140 59 13 Solution 2 144.8 108.0 1.7 0.5 6.9 33.0 1.375 30 5 Solution 3 146.2 108.0 1.7 0.5 6.9 33.0 2.6 75 29 5 Solution 4144.8 108.0 1.7 0.5 6.9 33.0 1.2 194 84 16 Solution 5 146.2 108.0 1.70.5 6.9 33.0 2.5 199 72 11

The particle counts were made by with the help of a HIAC Model 9703Liquid Particle Counting System (serie No. F08504) with the softwareversion Pharm, Spec. 1,4.

As evident from the results above in table 6, the resultingready-for-use solutions according to the invention is well under thelimits given in the European Pharmacopoeia.

Example 2

In order to find out the optimal pH ranges for the ready-for-usesolution in order to keep the formation of particles to a minimum thefollowing pair of single solutions according to table 7 was prepared andmixed. The volume relation between the first single solution and thesecond single solution is 1:20.

TABLE 7 Mixed First single solution Second single solution ready-for-use(basic part) (acid part) solution (mM) (mM) (mM) Na⁺ 1461.0 70.5 143.6Cl⁻ — 113.6* 108.0 Ca²⁺ — 1.8 1.7 Mg²⁺ — 0.5 0.5 HCO₃ ⁻ 139.0 — 6.9 CO₃²⁻ 661.0 — 33.0 *Chloride ions have been added as NaCl, CaCl₂, MgCl₂,and HCl.

The mixed solution was split in two parts, and 1.3 mM NaH₂PO₄ were addedto one part and 2.6 mM NaH₂PO₄ were added to the other part. The twodifferent solutions were pooled in 50 ml glass bottles and in each groupof bottles with the two different concentrations of NaH₂PO₄ the pH wasadjusted to 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, and 8.2. The amount ofparticles was measured 24 hours later.

In the enclosed FIGS. 1A-1C the results from this measurements are seenfor the solution containing 1.3 mM phosphate. In the enclosed FIGS.2A-2B the results form this measurements are seen for the solutioncontaining 2.6 mM phosphate.

As evident from the figures, the pH in a ready-for-use solution with aphosphate concentration of 1.3 mM should be below or equal to 7.6,preferably below or equal to 7.4. In a ready-for-use solution with aphosphate concentration of 2.6 mM the pH should be below or equal to7.4, preferably below or equal to 7.2. Particle formation is normallyfirst observed in the very small size and than they aggregate and formlarger particles. The chosen pH upper limits of 7.4 and 7.6,respectively, is based on changes in the particle profile rather than onabsolute values. All measured particle sizes where included in theevaluation with some extra focus on the small particles preceding theformation of larger particles.

Example 3

In order to find out the optimal upper limit for the phosphateconcentration for the ready-for-use solution in order to keep theformation of particles to a minimum, the following pair of singlesolutions according to table 8 was prepared. The volume relationshipbetween the first and the second single solution was 1:20.

TABLE 8 Mixed First single solution Second single solution ready-for-use(basic part) (acid part) solution (mM) (mM) (mM) Na⁺ 1461.0 70.5 143.6Cl⁻ — 113.6* 108.0 Ca²⁺ — 1.8 1.7 Mg²⁺ — 0.5 0.5 HCO₃ ⁻ 139.0 — 6.9 CO₃²⁻ 661.0 — 33.0 *Chloride ions have been added as NaCl, CaCl₂, MgCl₂,and HCl.

The first and second single solutions were mixed and split in 5different parts and phosphate was added in the following concentrations2.6, 2.8, 3.0, 3.5 and 4.0. pH was adjusted to 7.6 and the amount ofparticles was measured at 0 hour and 24 hours after mixing.

The results are shown in FIG. 3A-C, and from the figures it could beconcluded that the solution is stable during 24 hours at a phosphateconcentration less or equal to 2.8 mM phosphate and a pH of 7.6.

Accordingly, by having a phosphate concentration of 1.0-2.8 in a finalready-for-use solution with a pH of 6.5-7.6 a sterile, stable phosphatecontaining medical solution could be provided.

Example 4

The following pairs of single solutions were prepared according to thetables 9-11 and constitute different embodiments of the presentinvention. The volume relationship between the first single solution andthe second single solution in these pairs of solutions are 20:1.Accordingly, this time the second single solution has the small volumeand the first single solution has the larger volume.

TABLE 9 Mixed First single solution Second single solution ready-for-use(basic part) (acid part) solution (mM) (mM) (mM) Na⁺¹⁾ 147.3 140.0 Ca²⁺25.0 1.25 Mg²⁺ 12.0 0.6 K⁺ 4.21 4.0 Cl⁻²⁾ 114.3 74.0 115.9 HCO₃ ⁻34.74⁴⁾ 30.0 Lactate 0 HPO₄ ²⁻³⁾ 1.26 1.20 Glucose 100.0 5.00 HCl 72.0pH 7.7-8.2 1.3-1.6 7.0-7.6 ¹⁾Sodium is added as NaCl, NaHCO₃, andNa₂HPO₄. ²⁾Chloride is added as NaCl, KCl, CaCl₂, MgCl₂ and HCl.³⁾Phosphate is added as Na₂HPO₄, but after mixing the two singlesolutions it will be present mainly as HPO₄ ²⁻. However, H₂PO₄ ⁻ and PO₃³⁻ will also be present due to the equilibrium between these ions. Theconcentration of each ion will depend on the pH. ⁴⁾The amount ofbicarbonate is overdosed, since some bicarbonate will convert to CO₂during mixing and thus leave the solution.

TABLE 10 Second First single solution single solution Mixedready-for-use (basic part) (acid part) solution (mM) (mM) (mM) Na⁺¹⁾147.4 140.0 Ca²⁺ 30.0 1.5 Mg²⁺ 10.0 0.5 K⁺ 0 Cl⁻²⁾ 104.8 80.0 107.2 HCO₃⁻ 40.0⁴⁾ 35.0 Lactate 0 HPO₄ ²⁻³⁾ 1.26 1.2 Glucose 0 HCl 72.0 pH 7.7-8.31.3-1.6 7.0-7.6 ¹⁾Sodium is added as NaCl, NaHCO₃, Na₂HPO₄ and sodiumlactate. ²⁾Chloride is added as NaCl, CaCl₂, MgCl₂ and HCl. ³⁾Phosphateis added as Na₂HPO₄, but after mixing the two single solutions it willbe present mainly as HPO₄ ²⁻. However, H₂PO₄ ⁻ and PO₃ ³⁻ will also bepresent due to the equilibrium between these ions. The concentration ofeach ion will depend on the pH. ⁴⁾The amount of bicarbonate isoverdosed, since some bicarbonate will convert to CO₂ during mixing andthus leave the solution.

TABLE 11 Second First single solution single solution Mixedready-for-use (basic part) (acid part) solution (mM) (mM) (mM) Na⁺¹⁾147.4 140.0 Ca²⁺ 25.0 1.25 Mg²⁺ 12.0 0.6 K⁺ 4.2 4.0 Cl⁻²⁾ 149.1 74.0145.9 HCO₃ ⁻ 0 Lactate 36.8 35.0 HPO₄ ²⁻³⁾ 1.26 1.2 Glucose 100.0 5.0HCl 12.0 pH 7.4-7.9 1.9-2.2 6.5-7.0 ¹⁾Sodium is added as NaCl,, Na₂HPO₄and sodium lactate. ²⁾Chloride is added as NaCl, CaCl₂, MgCl₂ and HCl.³⁾Phosphate is added as Na₂HPO₄, but after mixing the two singlesolutions it will be present mainly as HPO₄ ²⁻. However, H₂PO⁴⁻ and PO₃³⁻ will also be present due to the equilibrium between these ions. Theconcentration of each ion will depend on the pH.

Example 5

The following pair of single solutions was prepared according to thetable 12 and constitutes an embodiment of the present invention. Thevolume relationship between the first single solution and the secondsingle solution in this pair is 1:20.

TABLE 12 Second First single solution single solution Mixedready-for-use (basic part) (acid part) solution (mM) (mM) (mM) Na⁺¹⁾1256 81.25 140 Ca²⁺ 1.32 1.25 Mg²⁺ 0.63 0.6 K⁺ 4.21 4 Cl⁻²⁾ 121 114.9HCO₃ ⁻ 132 6.6 CO₃ ²⁻ 538 26.9 HPO₄ ²⁻³⁾ 24 1.2 Glucose 5.26 5.00 (0.9g/l) HCl 31.6 pH 10.3 1.5 7.25 ¹⁾Sodium is added as NaCl, NaHCO₃,Na₂CO₃, and Na₂HPO₄. ²⁾Chloride is added as NaCl, KCl, CaCl₂, MgCl₂ andHCl. ³⁾Phosphate is added as Na₂HPO₄, but after mixing the two singlesolutions it will be present mainly as HPO₄ ²⁻. However, H₂PO⁴⁻and PO₃³⁻ will also be present due to the equilibrium between these ions. Theconcentration of each ion will depend on the pH.

It should be understood that various changes and modifications to thepresently preferred embodiments described herein will be apparent tothose skilled in the art. Such changes and modifications can be madewithout departing from the spirit and scope of the present invention andwithout diminishing its attendant advantages. It is therefore intendedthat such changes and modifications be covered by the appended claims.

1-23. (canceled)
 24. A two-part medical solution comprising a first single solution and a second single solution, wherein said first single solution comprises at least one buffer chosen from the group of acetate, lactate, citrate, pyruvate, carbonate and bicarbonate; wherein said second single solution comprises an acid; wherein said first and/or second single solutions further comprise phosphate ions; wherein said first and second single solutions, after terminal sterilization and upon use, can be mixed together to form a ready-for-use medical solution; and wherein the ready-for-use medical solution comprises phosphate in a concentration of 1.0-2.8 mM, and said medical solution is sterile and has a pH of 6.5-7.6.
 25. A two-part medical solution according to claim 24, wherein the formed ready-for-use medical solution comprises phosphate in a concentration of 1.2-2.6 mM.
 26. A two-part medical solution according to claim 24, wherein the formed ready-for-use medical solution has a pH of 6.5-7.4.
 27. A two-part medical solution according to claim 24, wherein the formed ready-for-use medical solution comprises phosphate in a concentration of 1.0-1.3 mM.
 28. A two-part medical solution according to claim 24, wherein said second single solution has a pH below 2.5.
 29. A two-part medical solution according to claim 24, wherein said first single solution comprises bicarbonate and carbonate in such proportions that the partial pressure of carbon dioxide in the first single solution is of the same order of magnitude as the partial pressure of carbon dioxide in the atmosphere, said second single solution having a pH of 1.0-1.5, and said medical solution having a pH of 7.0-7.6.
 30. A two-part medical solution according to claim 24, wherein said first single solution has a pH of 10.1-10.5.
 31. A two-part medical solution according to claim 24, wherein said first single solution has a pH of 10.3.
 32. A two-part medical solution according to claim 24, wherein said second single solution has a pH of 1.3.
 33. A two-part medical solution according to claim 24, wherein said second single solution comprises HCl.
 34. A two-part medical solution according to claim 24, wherein the formed ready-for-use medical solution further comprises one or more electrolytes.
 35. A two-part medical solution according to claim 34, wherein said one or more electrolytes comprise one or more ions of sodium, calcium, potassium, magnesium or chloride.
 36. A two-part medical solution according to claim 35, wherein sodium or chloride, or sodium and chloride, before being mixed into the ready-for-use medical solution, are arranged both in said first and second single solutions.
 37. A two-part medical solution according to claim 34, wherein the one or more electrolytes, before being mixed into the ready-for-use medical solution, are arranged in said second single solution.
 38. A two-part medical solution according to claim 37, wherein sodium or chloride, or sodium and chloride, before being mixed into the ready-for-use medical solution, are arranged in said second single solution.
 39. A two-part medical solution according to claim 24, wherein said first single solution comprises bicarbonate and phosphate, and said second single solution comprises calcium or magnesium, or calcium and magnesium.
 40. A two-part medical solution according to claim 39, wherein said first single solution comprises lactate and phosphate, and said second single solution comprises calcium or magnesium, or calcium and magnesium.
 41. A two-part medical solution according to claim 24, wherein said second single solution further comprises glucose or glucose-like compounds.
 42. A method for producing a two-part medical solution according to claim 1, said method comprising the steps of: providing said at least first and second single solutions in separate compartments, and terminally sterilizing said at least first and second single solutions.
 43. A multi-compartment bag comprising the two-part medical solution according to claim
 24. 